Methods and devices for treating conditions associated with autonomic dysfunction

ABSTRACT

Methods and devices treating an autonomic nervous system associated disease condition in a subject are provided. Aspects of the invention include inducing one or more physiological response selected from the group consisting of sweating, gastric emptying, enhanced heart rate variability and enhanced quantitative sensory test responsiveness in a manner sufficient to modify the autonomic nervous system so as to treat the subject for the disease condition. The methods and devices find use in a variety of applications, e.g. in the treatment of subjects suffering from conditions arising from disorders of the autonomic nervous system.

CROSS-REFERENCE TO RELATED APPLICATIONS

Pursuant to 35 U.S.C. §119 (e), this application claims priority to thefiling date of U.S. Provisional Patent Application Ser. No. 61/526,609filed Aug. 23, 2011; the disclosure of which is herein incorporated byreference.

INTRODUCTION

Dysautonomia (autonomic dysfunction) is a broad term that describes anydisease or malfunction of the autonomic nervous system. This includespostural orthostatic tachycardia syndrome (POTS), inappropriate sinustachycardia (IST), vasovagal syncope, mitral valve prolapsedysautonomia, pure autonomic failure, neurocardiogenic syncope (NCS),neurally mediated hypotension (NMH), autonomic instability and a numberof lesser-known disorders such as cerebral salt-wasting syndrome.

There is continued interest in the development of new methodologies fortreating autonomic dysfunction and related conditions.

SUMMARY

Methods and devices treating an autonomic nervous system associateddisease condition in a subject are provided. Aspects of the inventioninclude inducing one or more physiological response selected from thegroup consisting of sweating, gastric emptying, enhanced heart ratevariability and enhanced quantitative sensory test responsiveness in amanner sufficient to modify the autonomic nervous system so as to treatthe subject for the disease condition. The methods and devices find usein a variety of applications, e.g. in the treatment of subjectssuffering from conditions arising from disorders of the autonomicnervous system.

DETAILED DESCRIPTION

Methods and devices treating an autonomic nervous system associateddisease condition in a subject are provided. Aspects of the inventioninclude inducing one or more physiological response selected from thegroup consisting of sweating, gastric emptying, enhanced heart ratevariability and enhanced quantitative sensory test responsiveness in amanner sufficient to modify the autonomic nervous system so as to treatthe subject for the disease condition. The methods and devices find usein a variety of applications, e.g. in the treatment of subjectssuffering from conditions arising from disorders of the autonomicnervous system.

Before the present invention is described in greater detail, it is to beunderstood that this invention is not limited to particular embodimentsdescribed, as such may, of course, vary. It is also to be understoodthat the terminology used herein is for the purpose of describingparticular embodiments only, and is not intended to be limiting, sincethe scope of the present invention will be limited only by the appendedclaims.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range, is encompassed within the invention. The upper and lowerlimits of these smaller ranges may independently be included in thesmaller ranges and are also encompassed within the invention, subject toany specifically excluded limit in the stated range. Where the statedrange includes one or both of the limits, ranges excluding either orboth of those included limits are also included in the invention.

Certain ranges are presented herein with numerical values being precededby the term “about.” The term “about” is used herein to provide literalsupport for the exact number that it precedes, as well as a number thatis near to or approximately the number that the term precedes. Indetermining whether a number is near to or approximately a specificallyrecited number, the near or approximating unrecited number may be anumber which, in the context in which it is presented, provides thesubstantial equivalent of the specifically recited number.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the present invention, representativeillustrative methods and materials are now described.

All publications and patents cited in this specification are hereinincorporated by reference as if each individual publication or patentwere specifically and individually indicated to be incorporated byreference and are incorporated herein by reference to disclose anddescribe the methods and/or materials in connection with which thepublications are cited. The citation of any publication is for itsdisclosure prior to the filing date and should not be construed as anadmission that the present invention is not entitled to antedate suchpublication by virtue of prior invention. Further, the dates ofpublication provided may be different from the actual publication dateswhich may need to be independently confirmed.

It is noted that, as used herein and in the appended claims, thesingular forms “a”, “an”, and “the” include plural referents unless thecontext clearly dictates otherwise. It is further noted that the claimsmay be drafted to exclude any optional element. As such, this statementis intended to serve as antecedent basis for use of such exclusiveterminology as “solely,” “only” and the like in connection with therecitation of claim elements, or use of a “negative” limitation.

As will be apparent to those of skill in the art upon reading thisdisclosure, each of the individual embodiments described and illustratedherein has discrete components and features which may be readilyseparated from or combined with the features of any of the other severalembodiments without departing from the scope or spirit of the presentinvention. Any recited method can be carried out in the order of eventsrecited or in any other order which is logically possible.

In further describing embodiments of the invention, aspects of themethods will be described first, followed by a review of aspects ofdevices for use in the subject methods, embodiments of applications inwhich the methods and devices find use, as well as kits for performingmethods of the invention.

Methods

Aspects of the invention include methods of treating a subject having acondition arising from autonomic dysfunction. As reviewed above,autonomic dysfunction, i.e., Dysautonomia, is a malfunction of theautonomic nervous system. As reviewed below, a variety of differentdiseases may be treated according to methods of the invention.

In practicing methods according to embodiments of the invention, aphysiological response is enhanced in a manner sufficient to modify theautonomic nervous system so as to treat the disease condition. By“enhanced” it is meant that the magnitude of the physiological response(examples of which are detailed below) is increased, e.g., by 2-fold ormore, such as 5-fold or more, including 10-fold or more, as compared toa suitable control.

The physiological response may vary and in some instances is selectedfrom the group consisting of: sweating, gastric emptying, heart ratevariability, ability to rapidly transition from prone to suspendedorientation, and quantitative sensory test responsiveness. Each of thesephysiological responses is now described in greater detail.

In some instances, methods of invention include enhancing sweating of asubject in a manner sufficient to modulate the subject's autonomicnervous system so as to treat the target disease condition. In certainof these embodiments, the methods include inducing sweating in thesubject. Sweating may be induced using any convenient protocol. In someinstances, the subject is subjected to whole body induction of sweating.In these instances, the entire body of the subject may be subjected toan increased temperature sufficient to induce whole body sweating. Forexample, the subject may be placed in a temperature controlled chamberand the temperature in the chamber elevated to a temperature sufficientto induce sweating, e.g., to a temperature ranging from 45 to 50° C.Where desired, sweat induction may be monitored in a region of thesubject's body or the subject entire body may be evaluated for sweatinduction, e.g., via thermoregulatory sweat testing (TST) protocols,e.g., as described in Illigens et al., Clin. Auton. Res. (2009)19:79-87. Instead of whole body sweat induction, localized sweatinduction may be employed. For example, Quantitative Sudomotor ReflexTest (QSART) protocols may be employed to locally induce sweating,wherein a cholinergic agent (such as acetylcholine, pilocarpine ormethacholine) is iontophoretically administered to a patient, e.g., thearm of a patient, and sweat induction is measured, e.g., with ahygrometer, e.g., as described in Illigens, supra. As a variation,instead of measuring sweat induction with a hygrometer, moldablematerials, e.g., silicone, may be employed, e.g., as described inIlligens, supra. In yet other embodiments, Quantitative Direct andIndirect Axon Reflex Testing (QDIRT) protocols may be employed.

As reviewed above, where the physiological response is sweating,sweating will be enhanced in the subject in a manner sufficient tomodulate the autonomic nervous system as desired. In some instances, thesweating is induced in a manner sufficient to achieve a desiredparasympathetic activity/sympathetic activity ratio, i.e., a desiredbalance between parasympathetic activity and sympathetic activity. Incertain embodiments the desired ratio is analogous to a parasympatheticactivity/sympathetic activity ratio observed in a healthy (i.e., asubject not experiencing an abnormality in the autonomic nervoussystem), “like” or rather analogous subject, e.g., a healthy humansubject ranging in age from about 20 years old to about 25 years old(subjects other than humans will have analogous age ranges). Forexample, if the subject being treated is a human subject, theparasympathetic activity/sympathetic activity ratio provided by thepractice of the subject methods may be analogous to the parasympatheticactivity/sympathetic activity ratio observed in a healthy human rangingin age from about 20 years old to about 25 years old.

To achieve the desired autonomic nervous system modulation, sweating maybe induced a single time or multiple times. Where a given course oftreatment (i.e., predetermined dosing schedule) includes induction ofsweating multiple times, sweating may be induced, e.g., as describedabove, and then the sweat stimulus may be removed, e.g., by cessation ofexposure to elevated temperature or cessation of administration of acholinergic agent. Following cessation stimulus, no additional stimulusis administered to the subject until the next time during the course oftreatment when sweating is to be induced. The duration of this periodbetween stimulus application, which may be referred to as a “holiday”period, may vary, but in certain embodiments is 1 day or longer, such as2 days or longer, including 5 days or longer, 10 days or longer, 15days, or longer. As such, embodiments of the methods include non-chronic(i.e., non-continuous) application of the stimulus. In certainembodiments, stimulus to the subject is done in an “irregularlyirregular” manner. As such, duration of the stimulus application events,as well as duration of holiday periods between such events, variesrandomly over the entire course of a treatment (which again ispredetermined), or at least a portion thereof. In addition, thevariation does not follow any pattern, but instead is random.

In some instances, methods of invention include enhancing gastricemptying of a subject in a manner sufficient to modulate the subject'sautonomic nervous system so as to treat the target disease condition. Incertain of these embodiments, the methods include inducing gastric inthe subject. Gastric emptying, i.e., the movement of food from thestomach to the small intestine, may be induced using any convenientprotocol. In some instances, electrical stimulation in the form ofgastric neurostimulation may be employed to induce gastric emptying.Devices suitable for use in gastric neurostimulation include, but arenot limited to: those described in U.S. Pat. Nos. 7,899,541; 7,363,084and 7,200,443; the disclosures of which are herein incorporated byreference. Alternatively, gastric emptying may be induced viapharmacological protocols, e.g., by administering metoclopramide(Reglan, Maxolon, Clopra), cisapride (Propulsid), erythromycin (E-Mycin,Erythrocin, Ery-Tab, EES) and domperidone (Motilium), etc. Wheredesired, the induction of gastric emptying may be monitored, e.g., usingthe protocol described in Tang et al., Dis. Mon. (2011) 57:74-101.

As reviewed above, where the physiological response is gastric emptying,gastric emptying will be enhanced in the subject in a manner sufficientto modulate the autonomic nervous system as desired. In some instances,the gastric emptying is induced in a manner sufficient to achieve adesired parasympathetic activity/sympathetic activity ratio, i.e., adesired balance between parasympathetic activity and sympatheticactivity. In certain embodiments the desired ratio is analogous to aparasympathetic activity/sympathetic activity ratio observed in ahealthy (i.e., a subject not experiencing an abnormality in theautonomic nervous system), “like” or rather analogous subject, e.g., ahealthy human subject ranging in age from about 20 years old to about 25years old (subjects other than humans will have analogous age ranges).For example, if the subject being treated is a human subject, theparasympathetic activity/sympathetic activity ratio provided by thepractice of the subject methods may be analogous to the parasympatheticactivity/sympathetic activity ratio observed in a healthy human rangingin age from about 20 years old to about 25 years old.

To achieve the desired autonomic nervous system modulation, gastricemptying may be induced a single time or multiple times. Where a givencourse of treatment (i.e., predetermined dosing schedule) includesinduction of gastric emptying multiple times, gastric emptying may beinduced, e.g., as described above, and then the stimulus may be removed,e.g., by cessation of application of electrical stimulation or cessationof administration of pharmacological agent. Following cessation ofstimulus, no additional stimulus is administered to the subject untilthe next time during the course of treatment when gastric emptying is tobe induced. The duration of this period between stimulus application,which may be referred to as a “holiday” period, may vary, but in certainembodiments is 1 hour or longer, e.g., 2 hours or longer, including 3hours or longer, e.g., 6 hours or longer, 12 hours or longer, 1 day orlonger, such as 2 days or longer, including 5 days or longer, 10 days orlonger, 15 days, or longer. As such, embodiments of the methods includenon-chronic (i.e., non-continuous) application of the stimulus. Incertain embodiments, stimulus to the subject is done in an “irregularlyirregular” manner. As such, duration of the stimulus application events,as well as duration of holiday periods between such events, variesrandomly over the entire course of a treatment (which again ispredetermined), or at least a portion thereof. In addition, thevariation does not follow any pattern, but instead is random.

In some instances, methods of invention include enhancing heart ratevariability (i.e., variation in interval between heart beats) of asubject in a manner sufficient to modulate the subject's autonomicnervous system so as to treat the target disease condition. Anyconvenient protocol may be employed for enhancing heart ratevariability, where suitable protocols include electrical stimulationprotocols, e.g., where an implantable pulse generator is employed tocause heart contraction according to a predetermined protocol thatenhances heart rate variability in a desired manner. Enhancement ofheart rate variability may be monitored using any convenient protocol,e.g., ECG, blood pressure, and the pulse wave signal derived from aphotoplethysmograph (PPG).

As reviewed above, where the physiological response is heart ratevariability, heart rate variability will be enhanced in the subject in amanner sufficient to modulate the autonomic nervous system as desired.In some instances, the enhancement of heart rate variability is producedin a manner sufficient to achieve a desired parasympatheticactivity/sympathetic activity ratio, i.e., a desired balance betweenparasympathetic activity and sympathetic activity. In certainembodiments the desired ratio is analogous to a parasympatheticactivity/sympathetic activity ratio observed in a healthy (i.e., asubject not experiencing an abnormality in the autonomic nervoussystem), “like” or rather analogous subject, e.g., a healthy humansubject ranging in age from about 20 years old to about 25 years old(subjects other than humans will have analogous age ranges). Forexample, if the subject being treated is a human subject, theparasympathetic activity/sympathetic activity ratio provided by thepractice of the subject methods may be analogous to the parasympatheticactivity/sympathetic activity ratio observed in a healthy human rangingin age from about 20 years old to about 25 years old.

To achieve the desired autonomic nervous system modulation, heart ratevariability may be enhanced a single time or multiple times. Where agiven course of treatment (i.e., predetermined dosing schedule) includesenhancement of heart rate variability multiple times, heart ratevariability may be enhanced e.g., as described above, and then thestimulus causing the enhancement in heart rate variability may beremoved, e.g., by cessation of application of electrical stimulation.Following cessation of stimulus, no additional stimulus is administeredto the subject until the next time during the course of treatment whenheart rate variability is to be enhanced. The duration of this periodbetween stimulus application, which may be referred to as a “holiday”period, may vary, but in certain embodiments is 1 hour or longer, e.g.,2 hours or longer, including 3 hours or longer, e.g., 6 hours or longer,12 hours or longer, 1 day or longer, such as 2 days or longer, including5 days or longer, 10 days or longer, 15 days, or longer. As such,embodiments of the methods include non-chronic (i.e., non-continuous)application of the stimulus. In certain embodiments, stimulus to thesubject is done in an “irregularly irregular” manner. As such, durationof the stimulus application events, as well as duration of holidayperiods between such events, varies randomly over the entire course of atreatment (which again is predetermined), or at least a portion thereof.In addition, the variation does not follow any pattern, but instead israndom.

In some instances, methods of invention include enhancing the ability ofa subject to rapidly transition from prone to suspended orientation in amanner sufficient to modulate the subject's autonomic nervous system soas to treat the target disease condition. In some instances, the abilityof a subject to withstand rapid transition from a prone to suspendedorientation without experiencing adverse effects, e.g., syncope, isenhanced. Any convenient protocol may be employed for enhancing theability of the subject to rapidly transition from prone to suspendedorientation, where suitable protocols rapid transition from prone tosuspended (e.g., 60 to 80°) orientations, e.g., as performed duringtilt-table tests, e.g., as described in Cliche & Cusson, CMAJ (2001)164:372-376. In some instances, pharmacological agents may be employed,e.g., syncope susceptibility agents, such as such as glyceryl trinitrateor isoproterenol.

As reviewed above, where the physiological response is ability torapidly transition from prone to suspended orientation, ability torapidly transition from prone to suspended orientation will be enhancedin the subject in a manner sufficient to modulate the autonomic nervoussystem as desired. In some instances, the enhancement of ability torapidly transition from prone to suspended orientation is produced in amanner sufficient to achieve a desired parasympatheticactivity/sympathetic activity ratio, i.e., a desired balance betweenparasympathetic activity and sympathetic activity. In certainembodiments the desired ratio is analogous to a parasympatheticactivity/sympathetic activity ratio observed in a healthy (i.e., asubject not experiencing an abnormality in the autonomic nervoussystem), “like” or rather analogous subject, e.g., a healthy humansubject ranging in age from about 20 years old to about 25 years old(subjects other than humans will have analogous age ranges). Forexample, if the subject being treated is a human subject, theparasympathetic activity/sympathetic activity ratio provided by thepractice of the subject methods may be analogous to the parasympatheticactivity/sympathetic activity ratio observed in a healthy human rangingin age from about 20 years old to about 25 years old.

To achieve the desired autonomic nervous system modulation, ability torapidly transition from prone to suspended orientation may be enhanced asingle time or multiple times. Where a given course of treatment (i.e.,predetermined dosing schedule) includes enhancement of ability torapidly transition from prone to suspended orientation, ability torapidly transition from prone to suspended orientation variability maybe enhanced e.g., as described above, and then the stimulus causing theenhancement in ability to rapidly transition from prone to suspendedorientation may be removed, e.g., by cessation of application ofelectrical stimulation. Following cessation of stimulus, no additionalstimulus is administered to the subject until the next time during thecourse of treatment when heart rate variability is to be enhanced. Theduration of this period between stimulus application, which may bereferred to as a “holiday” period, may vary, but in certain embodimentsis 1 hour or longer, e.g., 2 hours or longer, including 3 hours orlonger, e.g., 6 hours or longer, 12 hours or longer, 1 day or longer,such as 2 days or longer, including 5 days or longer, 10 days or longer,15 days, or longer. As such, embodiments of the methods includenon-chronic (i.e., non-continuous) application of the stimulus. Incertain embodiments, stimulus to the subject is done in an “irregularlyirregular” manner. As such, duration of the stimulus application events,as well as duration of holiday periods between such events, variesrandomly over the entire course of a treatment (which again ispredetermined), or at least a portion thereof. In addition, thevariation does not follow any pattern, but instead is random.

In some instances, methods of invention include enhancing quantitativesensory test (QST) responsiveness of a subject in a manner sufficient tomodulate the subject's autonomic nervous system so as to treat thetarget disease condition. Any convenient protocol may be employed forenhancing QST responsiveness, where suitable protocols includestimulating the subject with a suitable stimulus, e.g., vibration orheat, e.g., as described in Chong and Cros, Muscle Nerve (2004)29:734-747.

As reviewed above, where the physiological response is QSTresponsiveness, QST responsiveness will be enhanced in the subject in amanner sufficient to modulate the autonomic nervous system as desired.In some instances, the enhancement of QST responsiveness is produced ina manner sufficient to achieve a desired parasympatheticactivity/sympathetic activity ratio, i.e., a desired balance betweenparasympathetic activity and sympathetic activity. In certainembodiments the desired ratio is analogous to a parasympatheticactivity/sympathetic activity ratio observed in a healthy (i.e., asubject not experiencing an abnormality in the autonomic nervoussystem), “like” or rather analogous subject, e.g., a healthy humansubject ranging in age from about 20 years old to about 25 years old(subjects other than humans will have analogous age ranges). Forexample, if the subject being treated is a human subject, theparasympathetic activity/sympathetic activity ratio provided by thepractice of the subject methods may be analogous to the parasympatheticactivity/sympathetic activity ratio observed in a healthy human rangingin age from about 20 years old to about 25 years old.

To achieve the desired autonomic nervous system modulation, QSTresponsiveness may be enhanced a single time or multiple times. Where agiven course of treatment (i.e., predetermined dosing schedule) includesenhancement of QST responsiveness multiple times, QST responsiveness maybe enhanced e.g., as described above, and then the stimulus causing theenhancement in QST responsiveness may be removed, e.g., by cessation ofapplication of vibration or temperature change. Following cessation ofstimulus, no additional stimulus is administered to the subject untilthe next time during the course of treatment when heart rate variabilityis to be enhanced. The duration of this period between stimulusapplication, which may be referred to as a “holiday” period, may vary,but in certain embodiments is 1 hour or longer, e.g., 2 hours or longer,including 3 hours or longer, e.g., 6 hours or longer, 12 hours orlonger, 1 day or longer, such as 2 days or longer, including 5 days orlonger, 10 days or longer, 15 days, or longer. As such, embodiments ofthe methods include non-chronic (i.e., non-continuous) application ofthe stimulus. In certain embodiments, stimulus to the subject is done inan “irregularly irregular” manner. As such, duration of the stimulusapplication events, as well as duration of holiday periods between suchevents, varies randomly over the entire course of a treatment (whichagain is predetermined), or at least a portion thereof. In addition, thevariation does not follow any pattern, but instead is random.

Utility

The subject methods find use in a variety of applications in which it isdesired to treat a subject for a condition, e.g., a condition at leastinfluenced by an abnormality in the subject's autonomic nervous system.In such methods, at least a portion of a subject's autonomic nervoussystem is modulated in a manner suitable to treat the subject for thecondition, e.g., in a manner to increase the parasympatheticactivity/sympathetic activity ratio or decrease the parasympatheticactivity/sympathetic activity ratio in certain embodiments. As indicatedabove, in many embodiments of this type of application, the subjectmethods are employed to treat a condition in the subject in order toachieve a desired therapeutic outcome.

The subject methods find use in the treatment of a variety of differentconditions in which an abnormality in a subject's autonomic nervoussystem exists. By treatment is meant that at least an amelioration ofthe symptoms associated with the condition afflicting the subject isachieved, where amelioration is used in a broad sense to refer to atleast a reduction in the magnitude of a parameter, e.g. symptom,associated with the condition being treated. As such, treatment alsoincludes situations where the condition, or at least symptoms associatedtherewith, are completely inhibited, e.g. prevented from happening, orstopped, e.g. terminated, such that the subject no longer suffers fromthe condition, or at least the symptoms that characterize the condition.In certain embodiments, the condition being treated is a diseasecondition.

A variety of subjects are treatable according to the subject methods. Inmany embodiments the subjects are “mammals” or “mammalian,” where theseterms are used broadly to describe organisms which are within the classmammalia, including the orders carnivore (e.g., dogs and cats), rodentia(e.g., mice, guinea pigs, and rats), and primates (e.g., humans,chimpanzees, and monkeys). In many embodiments, the subjects are humans.

As noted above, abnormalities in a subject's autonomic nervous systeminclude those characterized by an abnormally high parasympatheticactivity or abnormally low parasympathetic activity and/or an abnormallyhigh sympathetic activity or abnormally low sympathetic activity.Certain abnormalities may be characterized by having normal activity inone of the systems of the autonomic nervous system (the parasympatheticsystem or sympathetic system), but which may have abnormal activity inthe other system (the parasympathetic system or sympathetic system).

The subject methods find use in the treatment of a variety of differentconditions, including, but not limited to: cardiovascular conditionsincluding cardiovascular disease, e.g., atherosclerosis, coronary arterydisease, hypertension, hyperlipidemia, eclampsia, pre-eclampsia,cardiomyopathy, volume retention, congestive heart failure, QT intervalprolongation, aortic dissection, aortic aneurysm, arterial aneurysm,arterial vasospasm, myocardial infarction, reperfusion syndrome,ischemia, sudden adult death syndrome, arrhythmia, fatal arrythmias,coronary syndromes, coronary vasospasm, sick sinus syndrome,bradycardia, tachycardia, thromboembolic disease, deep vein thrombosis,coagulopathy, disseminated intravascular coagulation (“DIC”), mesentericischemia, syncope, venous thrombosis, arterial thrombosis, malignanthypertension, secondary hypertension, primary pulmonary hypertension,secondary pulmonary hypertension, raynaud's, paroxysmal supraventriculartachycardia, and the like; neurodegenerative conditions includingneurodegenerative diseases, e.g., Alzheimer's Disease, Pick's Disease,Parkinson's Disease, dementia, delirium, amyotrophic lateral sclerosis,and the like; neuroinflammatory conditions including neuroinflammatorydiseases, e.g., viral meningitis, viral encephalitis, fungal meningitis,fungal encephalitis, multiple sclerosis, charcot joint, schizophrenia,myasthenia gravis, and the like; orthopedic inflammatory conditionsincluding orthopedic inflammatory diseases, e.g., osteoarthritis,inflammatory arthritis, regional idiopathic osteoporosis, reflexsympathetic dystrophy, Paget's disease, osteoporosis, antigen-inducedarthritis, juvenile chronic arthritis, and the like; lymphoproliferativeconditions including lymphoproliferative diseases, e.g., lymphoma,lymphoproliferative disease, Hodgkin's disease, inflammatory pseudomotorof the liver, and the like; autoimmune conditions including automimmunediseases, e.g., Graves disease, raynaud's, hashimoto's, takayasu'sdisease, kawasaki's diseases, arteritis, scleroderma, CREST syndrome,allergies, dermatitis, Henoch-schlonlein purpura, goodpasture syndrome,autoimmune thyroiditis, myasthenia gravis, Reiter's disease, lupus, andthe like; inflammatory conditions, e.g., acute respiratory distresssyndrome (“ARDS”), multiple sclerosis, rheumatoid arthritis, juvenilerheumatoid arthritis, juvenile chronic arthritis, migraines, chronicheadaches, and the like; infectious diseases, e.g., sepsis, viral andfungal infections, diseases of wound healing, wound healing,tuberculosis, infection, AIDS, human immunodeficiency virus, and thelike; pulmonary conditions including pulmonary diseases, e.g.,tachypnea, fibrotic lung diseases such as cystic fibrosis and the like,interstitial lung disease, desquamative interstitial pneumonitis,non-specific interstitial pneumonitis, intrapulmonary shunts;lymphocytic interstitial pneumonitis, usual interstitial pneumonitis,idiopathic pulmonary fibrosis, pulmonary edema, aspiration,asphyxiation, pneumothorax, right-to-left shunts, left-to-right shunts,respiratory failure, and the like; transplant-related conditions such astransplant related side effects such as transplant rejection,transplant-related tachycardia, transplant related renal failure,transplant related bowel dysmotility, transplant-related hyperreninemia,and the like; gastrointestinal conditions including gastrointestinaldiseases, e.g., hepatitis, xerostomia, bowel mobility, peptic ulcerdisease, constipation, ileus, irritable bowel syndrome, post-operativebowel dysmotility, inflammatory bowel disease, typhilitis,cholelethiasis, cholestasis, fecal incontinence, cyclic vomitingsyndrome, and the like; endocrine conditions including endocrinediseases, e.g., hypothyroidism, hyperglycemia, diabetes, obesity,syndrome X, insulin resistance, polycystic ovarian syndrome (“PCOS”),and the like; genitourinary conditions including genitourinary diseases,e.g., bladder dysfunction, renal failure, erectile dysfunction,hyperreninemia, hepatorenal syndrome, pulmonary renal syndrome,incontinence, arousal disorder, menopausal mood disorder, premenstrualmood disorder, renal tubular acidosis, pulmonary renal syndrome, and thelike; skin conditions including skin diseases, e.g., wrinkles, cutaneousvasculitis, psoriasis, rash; and the like; aging associated conditionsincluding aging associated diseases, e.g., shy dragers, multi-systematrophy, age related inflammation conditions, cancer, aging, and thelike; neurologic conditions including neurologic diseases such asepilepsy, depression, schizophrenia, seizures, stroke, insomnia,cerebral vascular accident, transient ischemic attacks, stress, bipolardisorder, concussions, post-concussive syndrome, cerebral vascularvasospasm, central sleep apnea, obstructive sleep apnea, sleepdisorders, headaches including chronic headaches, migraines, acutedisseminated encephalomyelitis (“ADEM”), and the like; pediatricconditions, including pediatric diseases, e.g., respiratory distresssyndrome, sudden infant death syndrome, hirschsprung disease,bronchopulmonary dysplasia, congenital megacolon, ananglionosis,juvenile rheumatoid arthritis, juvenile chronic arthritis, and the like;Th-2 dominant conditions including Th-2 dominant diseases, e.g.,typhilitis, osteoporosis, lymphoma, myasthenia gravis, lupus, and thelike; conditions, including diseases, that cause hypoxia, hypercarbia,hypercapnia, acidosis, acidemia, Chronic Obstructive Pulmonary Disease(“COPD”), emphysema, any chronic lung disease that causes acidosis,acute pulmonary embolism, sudden adult death syndrome (“SADS”), chronicpulmonary embolism, pleural effusion, cardiogenic pulmonary edema,non-cardiogenic pulmonary edema, acute respiratory distress syndrome(ARDS), neurogenic edema, hypercapnia, acidemia, asthma, renal tubular,asthma, acidosis, chronic lung diseases that cause hypoxia, hypercarbiaor hypercapnia, and the like; OB-GYN conditions including OB-GYNdiseases, e.g., amniotic fluid embolism, menopausal mood disorders,premenstrual mood disorders, pregnancy-related arrhythmias, fetal stresssyndrome, fetal hypoxia, amniotic fluid embolism, gestational diabetes,pre-term labor, cervical incompetence, fetal distress, peri-partummaternal mortality, peripartum cardiomyopathy, labor complications,premenstrual syndrome, dysmenorrheal, endometriosis, and the like;sudden death syndromes, e.g., sudden adult death syndrome, sudden infantdeath syndrome, and the like; menstrual related disorders, e.g., pelvicpain, dysmenorrheal, gastrointestinal disease, nausea, and the like;peripartum and pregnancy related conditions, e.g., peripartumcardiomyopathy, and the like; fibrosis; post-operative recoveryconditions such as post-operative pain, post-operative ileus,post-operative fever, post-operative nausea, and the like;post-procedural recovery conditions such as post-procedural pain, postprocedural ileus, post-procedural fever, post-procedural nausea, and thelike; chronic pain; trauma; hospitalization; glaucoma; male infertility;disorders of thermoregulation; respiratory sinus arrhythmia; VQmismatch; fibromyalgia; and the like.

Other conditions may also be treated in accordance with the subjectinvention. Embodiments of the subject invention include treating one ormore conditions, sequentially or at the same time, in accordance withthe subject invention. Further description of target disease conditionsis found in U.S. Pat. No. 7,149,574, and published U.S. patentapplications 2005/0021092 and 2005/0240241, incorporated herein byreference.

Devices

Aspects of the invention include devices and systems, including aphysiological response stimulator, e.g., electrical stimulator,pharmacological agent deliver device, etc., operatively coupled to acontroller configured to operate the device in a manner sufficient toenhance a physiological response in a manner sufficient to modify theautonomic nervous system so as to treat the subject for the diseasecondition, e.g., as described above. The systems of the inventioninclude an implantable device, such as an implantable pulse generator oran implantable pharmacological agent delivery device. Instead of animplantable device, the device may be configured to be stably associatedwith a topical surface of the subject, e.g., an iontophoretic device.The controller may be any suitable component, and may include a suitablecombination of hardware and software.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is readily apparent to those of ordinary skill in theart in light of the teachings of this invention that certain changes andmodifications may be made thereto without departing from the spirit orscope of the appended claims.

Accordingly, the preceding merely illustrates the principles of theinvention. It will be appreciated that those skilled in the art will beable to devise various arrangements which, although not explicitlydescribed or shown herein, embody the principles of the invention andare included within its spirit and scope. Furthermore, all examples andconditional language recited herein are principally intended to aid thereader in understanding the principles of the invention and the conceptscontributed by the inventors to furthering the art, and are to beconstrued as being without limitation to such specifically recitedexamples and conditions. Moreover, all statements herein recitingprinciples, aspects, and embodiments of the invention as well asspecific examples thereof, are intended to encompass both structural andfunctional equivalents thereof. Additionally, it is intended that suchequivalents include both currently known equivalents and equivalentsdeveloped in the future, i.e., any elements developed that perform thesame function, regardless of structure. The scope of the presentinvention, therefore, is not intended to be limited to the exemplaryembodiments shown and described herein. Rather, the scope and spirit ofpresent invention is embodied by the appended claims.

What is claimed is:
 1. A method of treating a subject having a conditionarising from autonomic dysfunction, the method comprising: enhancing oneor more physiological responses selected from the group consisting of:sweating, gastric emptying, heart rate variability, ability to rapidlytransition from prone to suspended orientation, and quantitative sensorytest responsiveness, in a manner sufficient to modify the autonomicnervous system so as to treat the subject for the disease condition byapplying a pharmacological stimulus, an electrical stimulus, a thermalstimulus, or a combination of stimuli thereof, to induce the one or morephysiological responses multiple times during a course of treatment. 2.The method according to claim 1, wherein the physiological response issweating.
 3. The method according to claim 2, wherein method compriseswhole body induction of sweating.
 4. The method according to claim 2,wherein the method comprises localized induction of sweating.
 5. Themethod according to claim 1, wherein the physiological response gastricemptying.
 6. The method according to claim 5, wherein the methodcomprises electrically stimulating gastric emptying.
 7. The methodaccording to claim 6, wherein the method comprises pharmacologicallystimulating gastric emptying.
 8. The method according to claim 1,wherein the physiological response is heart rate variability.
 9. Themethod according to claim 8, wherein enhancing comprises applying anelectrical stimulus to induce heart rate variability multiple timesduring the course of treatment.
 10. The method according to claim 8,wherein the enhancing comprises applying a pharmacological stimulus toinduce heart rate variability multiple times during the course oftreatment.
 11. The method according to claim 1, wherein thephysiological response is ability to rapidly transition from prone tosuspended orientation and the method comprises rapidly transitioning thesubject from a prone to suspended orientation.
 12. The method accordingto claim 1, wherein the physiological response is quantitative sensorytest responsiveness.
 13. The method according to claim 1, wherein thesubject is a mammalian subject.
 14. The method according to claim 13,wherein the mammalian subject is a human.
 15. The method according toclaim 1, wherein the method further comprises diagnosing the subject ashaving an autonomic nervous system condition.
 16. A device comprising: aphysiological response stimulator; and a controller configured tooperate the device in a manner sufficient to perform the methodaccording to claim
 1. 17. The device according to claim 16, wherein thedevice is an implantable device.
 18. The implantable device according toclaim 17, wherein the implantable device is an implantable pulsegenerator.
 19. The implantable device according to claim 17, wherein theimplantable device is an implantable active agent delivery device. 20.The device according to claim 16, wherein the device is configured to bestably associated with a topical surface of the subject.
 21. The deviceaccording to claim 20, wherein the device is configured to locallyinduce sweating in a subject.
 22. The method according to claim 1,wherein the treatment course comprises non-continuous application of thestimulus.
 23. The method according to claim 22, wherein thenon-continuous application of the stimulus comprises a holiday period.